skin manifestations of certain diseases

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Collagen V ascular D isease

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It is an Idiopathic inflammatory myopathy with characteristic cutaneous finding . It is a connective tissue disease being characterized by a triad of vasculitis , fibrinoid necrosis to connective tissue and degenration of muscle. Also known as Wagner - Unverricht syndrome after the wagner and unverricht first described the syndrome in the late 1880s Heinrich Unverricht Ernst Wagner

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Aetiology The exact aeitiology of dermatomyositis is obscure but the condition is suspected to be caused by : Auto-immunity Viral infection ( epstein-barr virus, echo,paro,coxsachie ) Statins,hydroxyurea , quinidine , penicillamine Paraneoplastic phenomenon

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Persons with dermatomyositis (DM) often present with skin disease as one of the initial manifestations. In perhaps as many as 40% of individuals with dermatomyositis , the skin disease is the sole manifestation at onset. Muscle disease may occur concurrently, may precede the skin disease, or may follow the skin disease by weeks to years . Individuals with dermatomyositis often notice an eruption on exposed surfaces. The rash is often pruritic , and intense pruritus may disturb sleep patterns. Patients may also report scaly scalp or diffuse hair loss Skin Manifestations Heliotrope rash : a violaceous -to-dusky erythematous rash with or without edema in a symmetrical distribution involving periorbital skin. Presentation Clinical

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Gottron papules : are found over bony prominences, particularly the metacarpophalangeal joints, the proximal interphalangeal joints, and/or the distal interphalangeal joints. Papules may also be found overlying the elbows, knees, and/or feet. The lesions consist of slightly elevated violaceous papules and plaques. A slight scale and, occasionally, a thick psoriasiform scale may be present.

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Nailfold changes consist of periungual telangiectases and/or a characteristic cuticular change with hypertrophy of the cuticle and small hemorrhagic infarcts with this hypertrophic area. Periungual telangiectases may be apparent clinically or may be visible only on capillary microscopy

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Poikiloderma : may occur on exposed skin, such as the extensor surfaces of the arm, and may appear in a V-shaped distribution over the anterior neck and upper chest and back ( ie , shawl sign).

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The eruption of dermatomyositis is photodistributed and photoexacerbated . Despite the prominent photodistribution of the rash, patients rarely report photosensitivity . Facial erythema may also occur in dermatomyositis . Scalp involvement in dermatomyositis is relatively common and manifests as an erythematous -to- violaceous psoriasiform dermatitis. Clinical distinction from seborrheic dermatitis or psoriasis is occasionally difficult. Nonscarring alopecia may occur in some patients and often follows a flare of systemic disease.

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Panniculitis , urticaria , and hyperkeratosis of the palms (known as mechanic's hands) are examples of these cutaneous lesions. Other findings include cutaneous mucinosis , follicular hyperkeratosis, hyperpigmentation , ichthyosis , white plaques on the buccal mucosa, cutaneous vasculitis , and flagellate erythema . Panniculitis Mechanic's hands Cutaneous mucinosis Ichthyosis

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Calcinosis : of the skin or muscle is unusual in adults with dermatomyositis but may occur in as many as 40% of children or adolescents with the disease. Calcinosis cutis manifests as firm, yellow- or flesh- colored nodules, often over bony prominences. Occasionally, the nodules extrude through the surface of the skin, in which case secondary infection may occur.

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Muscle enzyme levels are often abnormal The most sensitive/specific enzyme is elevated creatine kinase (CK), but aldolase studies and other tests ( eg , aspartate aminotransferase [AST], lactic dehydrogenase [LDH]) may also yield abnormal results. At times, the elevation of the enzymes precedes clinical evidence of myositis . Several serologic abnormalities like myositis -specific antibodies (MSAs). These autoantibodies occur in about 30% of all patients with dermatomyositis or polymyositis.A positive ANA finding is common in patients with dermatomyositis . Anti–Mi-2 antibodies are highly specific for dermatomyositis but lack sensitivity because only 25% of the patients with dermatomyositis demonstrate them. They are associated with acute-onset classic dermatomyositis with the V-shaped and shawl rash ( poikiloderma ) and a relatively good prognosis . Anti–Jo-1 ( antihistidyl transfer RNA [t-RNA] synthetase ) is more common in patients with polymyositis than in patients with dermatomyositis . It is associated with pulmonary involvement (interstitial lung disease), Raynaud phenomenon, arthritis, and mechanic's hands . MRI ,CHEST RADIOGRAPHY , ELECTROMYOGRAPHY AND MUSCLE BIOPSY Diagnosis

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Therapy for dermatomyositis (DM) involves general measures and measures to control both the muscle disease and the skin disease. In addition, some patients with dermatomyositis need treatment for other systemic manifestations or complications . General treatment Bedrest is often valuable in patients with severe muscle inflammation. In patients with muscle weakness, especially children, a program of physical therapy is useful to help prevent contractures that can complicate the disease when patients do not fully move their joints. For patients with dysphagia , recommending elevating the head of their bed and not eating before bedtime is useful, possibly preventing aspiration pneumonitis . Occasionally, nasogastric tube feeding is needed to increase caloric input . Treatment of muscle disease Corticosteroids . Traditionally, prednisone (1-2 mg/kg/d) is administered as initial therapy. Taper slowly to avoid relapse . Because most patients develop steroid-related toxic effects, many authorities begin an immunosuppressive or cytotoxic agent early in the course. Most clinical and published experience is with the use of methotrexate as a steroid-sparing agent, but azathioprine and mycophenolate mofetil have been used When these measures fail, the use of monthly high-dose intravenous immunoglobulin (IVIG) for 6 months has proved beneficial in the short term. In addition to its positive effects on refractory muscle and skin disease, IVIG has been reported to be beneficial for other systemic manifestations including severe esophageal dysfunction. [7 ] One report has suggested that rituximab , a chimeric antibody directed against CD20 + B cells, may be effective . T REATMENT

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Treatments for skin disease Therapy of cutaneous disease of dermatomyositis is often difficult. Some patients with dermatomyositis present primarily with skin disease ( ie , amyopathic dermatomyositis ), while other patients present with a muscle component that is controlled but with significant ongoing skin disease. First-line therapy is to recognize that the patient is photosensitive and to prescribe sun avoidance and sun protective measures, including broad-spectrum sunscreens . Hydroxychloroquine and chloroquine have been beneficial in small, open-label case studies; [8, 9] however, roughly 20% of patients with dermatomyositis who are treated with an antimalarial agent develop a drug eruption. Methotrexate is useful. Mycophenolate mofetil has been reported to be useful , Sirolimus may also be of use in some patients. In addition, small case series or individual reports of successful management with leflunomide have recently appeared in the literature. [16] IVIG not only benefits the muscle but also clears the skin lesions. Calcinosis This complication of dermatomyositis affects children and adolescents. Some believe that aggressive early treatment of the myositis may aid in preventing calcinosis . Once established, the process of calcinosis is debilitating in many patients. Although spontaneous remission is possible, it often occurs after many years. The use of the calcium channel blocker diltiazem (240 mg bid) is reportedly associated with gradual resolution of calcinosis in a small number of cases. [17] Colchicine , alendronate , and warfarin have also been shown to be potentially beneficial for the resolution of calcinosis

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The term lupus (Latin for wolf) is attributed to the thirteenth century physician Rogerius who used it to describe erosive facial lesions that were reminiscent of a wolf's bite. Also known as a ‘great imitator’ because of its multi-organ involvement . It is defined as a multiorgan system autoimmune connective tissue disease with numerous immunological and clinical manifestations. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens. The disease mainly involves the skin, joints, kidneys, blood cells, and nervous system.

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Aetiology The exact etiology of the disease is obscure . Following causes are suspected Genetics SLE may have a genetic link. SLE does run in families, multiple genes appear to influence a person's chance of developing lupus when triggered by environmental factors. The most important genes are located in the HLA region on chromosome 6 , where mutations may occur randomly ( de novo ) or may be inherited. HLA classes I and II contribute independently to increased risk of SLE. Other genes which contain risk variants for SLE are IRF5 , PTPN22 , STAT4 , CDKN1A , ITGAM , BLK , TNFSF4 and BANK1 .

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Environmental triggers The second mechanism may be due to environmental factors. These factors may not only exacerbate existing SLE conditions, but also trigger the initial onset. Researchers have sought to find a connection between certain infectious agents ( viruses and bacteria ), but no pathogen can be consistently linked to the disease. Occupational exposure - Silica, pesticides, mercury Sunlight Drug reactions Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness. Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped. More than 38 medications can cause this condition, the most common of which are procainamide , hydralazine , quinidine , and phenytoin .

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From the clinical point of view it has been described as “an overwhelming mass of organized confusion” CLINICAL PRESENTATION

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L = Lymphopenia , leukopenia , anemia , thrombocytopenia U = Urine abnormality as proteinuria or cellular casts P = _ leuropericarditis U = Ulcers of mouth S = Skin discoid or malar rash, photosensitivitiy A = Arthritis N = Neurologic Sx as seizure, psychosis A = Autoantibodies as ANA, Anti-DNA, ANti-Sm , Anti- CardioLipin Ab

Skin manifestations of SLE:

Skin manifestations of SLE Malar rash(butterfly rash) : Malar rash is a fixed erythema that spares the nasolabial folds. It is a butterfly rash that can be flat or raised over the cheeks and bridge of the nose. It also often involves the chin and ears.

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Discoid rash occurs in 20% of patients with SLE and can result in disfiguring scars. The discoid rash can present as erythematous patches with keratotic scaling over sun-exposed areas of the skin. Systemic manifestations of SLE may be absent .

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Alopecia : Scarring – discoid lesion Non-scarring – lupus hair is thin, fractured, frontal hairline . NON-SCARRING SCARRING

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Vascular : Raynaud’s phenomenon Raynaud’s phenomenon is a condition in which cold temperatures or strong emotions cause blood vessel spasms that block blood flow to the fingers, toes, ears, and nose .

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Livedo reticularis is a common vascular condition characterized by a net-like reddish-blue discoloration of the skin

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Periungual erythema Mucosal ulcers

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Photosensitivity

L.E. CELL:

L.E. CELL Historically, an abbreviation for lupus erythematosis cell, a polymorphonuclear leukocyte that contains the phagocytized nucleus of another cell. It is characteristic but not diagnostic of lupus erythematosus . This distinctive cell may form when the blood of patients with systemic lupus erythematosus is incubated and further processed according to a specified protocol. The plasma of some patients contains an antibody to the nucleoprotein of leukocytes. These altered nuclei, which are swollen, pink, and homogeneous, are ingested by phagocytes. These are the L.E. cells. The ingested material, when stained properly, is lavender and displaces the nucleus of the phagocyte to the inner surface of the cell membrane. The L.E. cell phenomenon can be demonstrated in most patients with systemic lupus erythematosus but is not essential for diagnosis

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LE C ell

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There is no cure for SLE.  Complete sustained remissions are rare. Goal of Rx: to control acute, severe flares and to develop maintenance strategies in which symptoms are suppressed to an acceptable level, usually at the cost of some drug side effects. Approximately 25% of SLE patients have mild disease with no life-threatening manifestations, although pain and fatigue may be disabling. These patients should be managed without glucocorticoids. Arthralgias , arthritis, myalgias , fever, and mild serositis may improve on nonsteroidal anti-inflammatory drugs ( NSAID s) including salicylates . The dermatitides of SLE, fatigue, and lupus arthritis may respond to antimalarials . Doses of 400 mg hydroxychloroquine daily may improve skin lesions in a few weeks. Side effects are uncommon and include retinal toxicity, rash, myopathy , and neuropathy. Regular ophthalmologic examinations should be performed at least annually, since retinal toxicity is related to cumulative dose. Other therapies include sunscreens (an SPF rating 15 is recommended), topical or intralesional glucocorticoids , quinacrine , retinoids , and dapsone . Recent studies suggest that daily oral doses of dihydroepiandrosterone may lower disease activity in patients with mild SLE. Systemic glucocorticoids should be reserved for patients with disabling disease unresponsive to these conservative measures. Life-threatening, severely disabling manifestations of SLE that are responsive to immunosuppression should be treated with high doses of glucocorticoids (1 to 2 mg/kg per day) . When disease is active, glucocorticoids should be given in divided doses every 8 to 12 h. Acutely ill lupus patients, including those with proliferative GN , can be treated with 3 to 5 days of 1000 mg intravenous "pulses" of methylprednisolone , followed by maintenance daily or alternate-day glucocorticoids . Disease flares are probably controlled more rapidly by this approach, but it is unclear whether long-term outcome is changed. The use of cytotoxic agents ( azathioprine , chlorambucil , cyclophosphamide , methotrexate , mycophenolate mofetil ) in SLE is probably beneficial in controlling active disease, reducing the rate of disease flares, and reducing steroid requirements. Patients with lupus nephritis have significantly less renal failure and better survival if treated with combinations of glucocorticoids plus intravenous cyclophosphamide ; azathioprine as the second drug is less beneficial but is also effective in preventing renal failure Teatment

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Scleroderma An idiopathic connective tissue disorder, characterized by localized or generalized induration of skin due to increased collagen deposition in skin, GI tract, lungs, heart, muscle, kidneys. Scleroderma is derived from the Greek words skleros (hard or indurated ) and derma (skin). Hippocrates first described this condition as thickened skin. [1] Carlo Curzio (1752) offered the first detailed description of scleroderma in a patient with hard skin, which he described as woodlike or as containing a dry hide. In 1836, Giovambattista Fantonetti applied the term scleroderma to a patient's condition

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High-power view of the characteristic histology of localized scleroderma depicting eccrine coils "trapped" in the deep dermis

Histology :

Histology NORMAL SKIN SCLERODERMA

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Underlying pathogenesis remains unclear. Interaction of the following 4 factors is believed to result in excessive production of collagen and lead to fibrosis: Host Genetic susceptibility Infection Environmental factors Microchimerism Vascular Endothelial-cell injury Vasoconstriction Vascular occlusion Tissue hypoxia Immune T-cell activation Macrophage activation Autoantibodies Cytokines Fibroblast Activation and growth Etiopathogenesis

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Skin Manifestations Skin tightness and induration : Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles, In the sclerotic phase, the skin may appear tight and shiny, with a characteristic loss of hair, decreased sweating, and loss of the ability to make a skin fold.

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Due to the severe skin tightening, there is autoamputation of the distal digits, contractures and skin ulceration.

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Sclerodactyl : with digital ulceration, loss of skin creases, joint contractures, and sparse hair.

Vascular system:

Vascular system Raynaud phenomenon (70% of patients with systemic sclerosis initially present with this symptom; 95% eventually develop it during the course of their disease)

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Skin pigmentary changes ( hyperpigmentation or hypopigmentation ) : Skin pigmentary changes include a salt-and-pepper appearance, with areas of hyperpigmentation alternating with hypopigmentation , or an overall appearance of tanned skin that persists long after sun exposure

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Healed pitting ulcers in fingertips Severe ulceration

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Cutaneous and mucosal telangiectasis Telangiectasias are dilated vessels located just beneath the dermis on any skin area, but they are most obvious in the face ( perioral area), hands, and anterior chest .

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The skin of the hands may be edematous or swollen early in the disease, and the patient may initially report this as puffy changes

SPLINTER HAEMORRAGES:

SPLINTER HAEMORRAGES

Microstomia :

Microstomia

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SKIN TUMOUR AND INTERNAL MALIGNANCIES

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In 1967, Muir and Torre each reported on patients with multiple cutaneous tumors (including sebaceous neoplasms and other tumors ) and visceral malignancies (including gastrointestinal and other sites). Muir-Torre syndrome (MTS) is a syndrome that combines at least one sebaceous neoplasm ( sebaceous adenoma , sebaceous epithelioma , or sebaceous carcinoma ) and at least one visceral malignancy (usually gastrointestinal or genitourinary carcinomas). Muir torre syndrome

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Muir-Torre syndrome (MTS) is considered a subtype of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC) The diagnostic criteria (Amsterdam criteria) include the following : Three or more relatives with an HNPCC-associated cancer ( ie , colorectal, cancer of the endometrium , small bowel, ureter , or renal pelvis) Cancer affecting at least 2 successive generations One person with cancer is a first-degree relative of the other 2, at least 1 case of colorectal cancer younger than age 50 years, a diagnosis of familial adenomatous polyposis has been excluded, tumors are verified by histologic examination

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The Skin lesions may precede the presentation of internal malignancy, although they often develop later. Sebaceous adenoma :These fairly rare benign tumors usually appear as yellow papules or nodules in adult patients. In the sporadic cases, most tumors are located on the head (particularly on the face, the scalp, and the eyelids), with the remaining minority scattered over the rest of the body. SKIN MANIFESTATIONS

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Sebaceous adenoma

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Sebaceous carcinomas most commonly occur on the eyelids, where they generally arise from the meibomian glands and the glands of Zeiss . They may also occur almost anywhere on the skin, including the ears, the feet, the penis, and the labia. On the eyelids, the tumor appears as a firm, yellow nodule with a tendency to ulcerate, as shown in the images below. Clinically, these lesions are often mistaken for chalazia , chronic blepharoconjunctivitis , or carbuncles. Sebaceous carcinoma of the eyelid can invade the orbit and can frequently metastasize and cause death. Extraocular tumors can also metastasize but are less likely to cause death.

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Sebaceous Carcinoma

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Gross image of an ear resection due to a deeply invasive sebaceous carcinoma

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Keratoacanthoma , whether solitary or multiple, is frequently seen in MTS. Keratoacanthoma usually starts as a red papule that rapidly grows to become a skin- colored , shiny nodule with telangiectases and a central horny plug covered by a crust. Common sites of involvement include the face and the dorsum of the hands, but they can occur anywhere on the body. The tumors have a tendency to regress, ultimately leaving a scar. Those keratoacanthoma cases with sebaceous differentiation are strongly associated with MTS.

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The most common visceral neoplasm in MTS is colorectal cancer , occurring in almost one half of patients. The tumors are usually proximal to the splenic flexure. The second most common site is the genitourinary tract, representing approximately one quarter of visceral cancers. A wide variety of other cancers, including breast cancer, lymphoma and rarely leukemia , salivary gland tumors , lower and upper respiratory tract tumors , and chondrosarcoma , are reported. Intestinal polyps occur in at least one quarter of patients. Other benign tumors described in MTS include ovarian granulosa cell tumor , hepatic angioma , benign schwannoma of the small bowel, and uterine leiomyomas .

TREATMENT:

TREATMENT Medical Care Oral isotretinoin can possibly prevent some of the neoplasms in persons with Muir-Torre syndrome (MTS). [20] A dosage of as much as 0.8 mg/kg/d may be effective. Combination of interferon with retinoids may be of promise to prevent cutaneous tumor development in persons with MTS.

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Surgical Care Benign sebaceous tumors and keratoacanthomas can be conservatively treated with excision or cryotherapy . Sebaceous carcinoma should be excised completely and followed-up for detection of possible metastases.

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“ This is the only clinical syndrome I know of which is named for a geneticist .” Gardner Syndrome . Eldon J. Gardner

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Gardner’s Syndrome Gardner syndrome, a variant of familial adenomatous polyposis (FAP) , is an autosomal dominant disease characterized by GI polyps, multiple osteomas , and skin and soft tissue tumors .

AETIOPATHOGENESIS:

AETIOPATHOGENESIS Gardner syndrome is genetically linked to band 5q21, the adenomatous polyposis coli locus

SKIN MANIFESTATIONS:

SKIN MANIFESTATIONS Multiple Skin polyp

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Cutaneous findings of Gardner syndrome include epidermoid cysts, desmoid tumors , and other benign tumors . Polyps have a 100% risk of undergoing malignant transformation; consequently, early identification of Gardner syndrome is critical Desmoid tumors Epidermoid cysts

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Pilomatrixoma Pilomatrixoma , also referred to as Malherbe's calcifying epithelioma , is a cyst derived from the hair matrix that forms the hair. It is often a solitary lesion and most commonly occurs on the face. Most pilomatrixomas occur in the first two decades of life and, if superficially located, produce a blue-red skin discoloration. Excision is curative.

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Other skin signs in Gardner syndrome include the following: Lipoma Fibromas

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Medical Care Treatment of the cutaneous manifestations of Gardner syndrome depends on the symptomatic or cosmetic nature and the location of the cysts. Treatment is similar to that used for ordinary cysts and involves excision [14] or use of intralesional steroids if the cysts are inflamed. Antiestrogens and anthracycline -containing regimens may have a favorable radiological response rate against desmoid tumors and may be a viable option in some patients. [15]

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Originally described in 1963 by Lloyd and Dennis, Cowden disease (multiple hamartoma syndrome) was named after the family in which it was first reported. an autosomal dominant condition with variable expression that results most commonly (80%) from a mutation in the PTEN gene on arm 10q, Cowden disease (multiple hamartoma syndrome) causes hamartomatous neoplasms of the skin and mucosa, GI tract, bones, CNS, eyes, and genitourinary tract. Skin is involved in 90-100% of cases, and the thyroid is involved in 66% of cases. It is associated with a high incidence of malignancies in the organs involved COWDEN SYNDROME

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Hamartoma ( hamartia - fault) A benign tumor like nodule composed of an owergrowth of mature cells and tissues that normally occur in the affected part but with disorganization and often with one element predominating

Skin Manifestations :

Skin Manifestations In 90-100% of patients, 1 of 4 types of mucocutaneous lesions is present. Cutaneous facial papules are present. Most patients exhibit either flesh- colored , flat-topped lichenoid , or elongated verrucoid papules. The lesions may have a central keratin-plugged center and a diameter ranging from 1-5 mm. Typically, large numbers of lesions are present and have a predisposition for the periorificial region. Most of these lesions are trichilemmomas

Multiple trichilemmomas in patient with Cowden disease.:

Multiple trichilemmomas in patient with Cowden disease.

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Oral lesions are common. Papules are 1-3 mm with a smooth surface and a whitish appearance and are present in the gingival, labial, and palatal surfaces of the mouth in more than 80% of patients. Lesions often coalesce into confluent sheets, which are described as having a cobblestone appearance

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Multiple benign oral fibromas Cobblestone

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Acral keratoses are flesh- colored or slightly pigmented smooth or verrucoid papules on the dorsal hands and feet, and they occur in more than 60% of patients. The lesions must be differentiated from verruca plana and acrokeratosis verruciformis .

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Palmoplantar keratoses are noted. Approximately 40% of Cowden disease (multiple hamartoma syndrome) patients have translucent punctate keratoses on the palms or soles. These need to be distinguished from benign keratoses and arsenic-induced keratoses .

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Other cutaneous lesions may occur. Less frequently noted lesions include Neuromas Hemangiomas Sclerotic fibromas Lipoma

Medication Summary :

Medication Summary Systemic therapy with retinoids may temporarily control some of the cutaneous lesions of Cowden disease (multiple hamartoma syndrome). Topical treatment usually is unsatisfactory. Rapamycin has shown great promise in both regression of cutaneous lesions and prevention of the development of manifestations of Cowden disease (multiple hamartoma syndrome) in a mouse model with a PTEN deletion. In the mouse model, rapamycin inhibited a key downstream target, mammalian target of rapamycin ( mTOR ), which caused rapid regression of Cowden disease (multiple hamartoma syndrome)–like lesions. [24] At this time, however, use of rapamycin , should be limited to clinical trials. A clinical trial is currently underway that is studying the effects of rapamycin on syndromes with PTEN mutations. Sirolimus is under clinical trial

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Multiple mucosal neuroma syndrome Multiple endocrine neoplasia type 2B (MEN 2B), or the mucosal neuroma syndrome, is an autosomal dominant hamartoneoplastic syndrome. Features include multiple mucosal neuromas , phaeochromocytoma , medullary thyroid carcinoma, and Marfanoid body habitus with a characteristic dysmorphic facies . Blubbery lip

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The gene responsible is the receptor tyrosine kinase (RET) proto-oncogene on chromosome 10.

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MEN type 2B disease carries a high risk for development of medullary carcinoma of the thyroid and phaeochromocytoma (a vascular tumour of the adrenal gland that may cause high blood pressure). MEN type 2B disease is also characterised by the development in early life of multiple mucosal neuromas . Neuromas appear as: Glistening bumps around the lips, tongue, and lining of the mouth Bumps on the eyelids which are often thickened – neuromas may also appear on the cornea and conjunctiva Growths in the gastrointestinal tract that may cause constipation, diarrhoea, and in some cases enlarged colon ( megacolon ). Patients with MEN type 2B disease also often develop spinal abnormalities, and abnormalities of the bones in the feet and thighs. Many have long limbs and loose joints. These features, along with thickened lips and eyelids are associated with Marfanoid habitus

Joseph Merrick, the Elephant Man :

Joseph Merrick, the Elephant Man

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Friedrich Daniel von Recklinghausen In 1882 Recklinghausen released a monograph which reviewed previous literature and characterized the tumors of Neurofibromatosis type I or NF-1 as neurofibromas , consisting of an intense commingling of nerve cells and fibrous tissue. NF-1 is sometimes referred to as von Recklinghausen syndrome. Neurofibromatosis is an autosomal dominant disorder that affects the bone, nervous system, soft tissue, and skin.

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Neurofibromatosis type 1 (NF 1) Neurofibromatosis type 2 (NF 2) CLASSIFICATION

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Schwannomatosis MRI of the right brachial plexus revealing two schwannomas (asterisks)

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NF 1

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NF 2

SKIN MANIFESTATIONS:

SKIN MANIFESTATIONS Café au lait spots Most individuals with neurofibromatosis have 6 or more café au lait spots that are 1.5 cm or greater in diameter The café au lait macules of neurofibromatosis have an even tan color and a smooth border neurofibroma

Neurofibromas :

Neurofibromas These tumors are composed of Schwann cells, fibroblasts, mast cells, and vascular components. They can develop at any point along a nerve. Three subtypes of neurofibroma exist: Cutaneous Subcutaneous Plexiform

Cutaneous and Subcutaneous neurofibroma :

Cutaneous and Subcutaneous neurofibroma Cutaneous lesions and subcutaneous lesions are circumscribed; neither is specific for type 1 neurofibromatosis. These nodules may be brown, pink, or skin colored . They may be soft or firm to the touch, and they may have the pathognomonic buttonhole invagination when pressed with a finger.

Plexiform neurofibromas:

Plexiform neurofibromas Plexiform neurofibromas are noncircumscribed , thick, and irregular, and they can cause disfigurement by entwining important supportive structures. The plexiform subtype is specific for type 1 neurofibromatosis.

Axillary freckling :

Axillary freckling Axillary freckling (as well as freckling on the perineum), known as the Crowe sign, is a helpful diagnostic feature in neurofibromatosis. Axillary freckling and inguinal freckling often develop during puberty

Medical Care :

Medical Care For individuals diagnosed with neurofibromatosis type 1 (NF1), routine examinations should focus on the potential complications.Annual examinations permit early detection of problems, decreasing morbidity and improving quality of life. Annual eye examinations are important in early detection of optic nerve lesions. Cutaneous examination performed at each visit should look for new neurofibromas or progression of preexisting lesions. Plexiform neurofibromas may be locally invasive, therefore clinical evaluation should be directed at determining the extent of involvement and detecting evidence of bony erosion or nerve entrapment. Blood pressure should be checked at each visit and hypertension treated promptly if detected. Hypertension workup should include evaluation for pheochromocytoma ( ie , measurement of urinary catecholamines and metanephrines ) and testing for renal artery stenosis . Percutaneous transluminal renal artery angioplasty may, in some cases, effectively treat renal artery stenosis secondary to fibromuscular dysplasia. Interval history should focus on subtle sensory or motor symptoms such as paresthesia , radiculopathy , weakness, or muscle atrophy.Patients should be asked about incontinence. At each visit, minor changes in the sensory or motor examination should be documented carefully.

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Removal of neurofibromas for medical or cosmetic indications is one of the most common procedures on individuals with NF1.Recent advances in laser technology have permitted nonsurgical removal of small, cutaneous neurofibromas . Use of chemotherapy to treat malignant peripheral nerve sheath tumors (MPNSTs) that are unresectable or metastatic has been debated for a number of years, with less than optimal outcomes using a variety of combinations of agents. More recently, in vitro studies looking at a broader range of agents targeting the Ras and/or other relevant pathways have shown some promising results .Farnesyl transferases used in combination with lovastatin have shown synergistic effects in growth inhibition of MPNST cell lines in vitro. [22] Sorafenib also appears to inhibit MPNST cell growth in vitro. [23] A rapamycin complex 1 inhibitor (RAD001) demonstrated decreased tumor cell growth when used alone, and, when used in combination with erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor), showed even further growth inhibition and tumor cell apoptosis. [24] Hyaluronan oligomers , another promising agent, has shown efficacy in slowing growth of MPNSTs in animal models. These small molecules, when used in combination with a traditional chemotherapy agent (doxorubicin), substantially inhibit tumor growth. [25]

Surgical care:

Surgical care Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention. Plexiform neurofibromas may be difficult to approach surgically, often recurring after resection because of residual tumor cell collections deep in soft tissues. Surgeons must realize that removing some of these lesions can result in substantial blood loss and must plan accordingly. Symptomatic peripheral nerve sheath tumors located along the nerves of the brachial or pelvic plexus sometimes require surgical intervention with the very real potential for postoperative nerve dysfunction. Added to this is the risk for malignant transformation that carries with it a very poor prognosis; the decision to operate requires much thought and careful consideration. One should always weigh the potential diagnostic benefits taking into account one's index of suspicion for malignancy, against the potential risks for long-term neurologic sequelae . For many patients, neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause great irritation and discomfort. Therefore, removing these should not be considered cosmetic but a necessary medical procedure. Resection of spinal cord tumors is difficult but often necessary to prevent progressive paraplegia or quadriplegia.

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Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.Following patients with NF1 when scoliosis is first detected is advisable, so that nonsurgical approaches may be used in an attempt to obviate the need for a future spinal fusion procedure. Limb-sparing procedures in addition to new bracing and casting technologies have decreased the need for amputation in patients with a pseudarthrosis .

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Patients with long-bone defects are best served by ongoing orthopedic care. Some hypertensive patients with renal artery stenosis require surgical resection and repair instead of or following angioplasty. Resection of a pheochromocytoma requires preoperative treatment with an alpha-blocker (preferably a selective postsynaptic alpha1-receptor antagonist) to offset the effects of catecholamine release during surgical manipulation of the tumor

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